NCOA4-Mediated Ferritinophagy in Iron-Dependent Brain Development

铁依赖性大脑发育中 NCOA4 介导的铁蛋白自噬

• 批准号: 10284640
• 负责人: Thomas W. Bastian
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-27 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284640
• 关键词: Acute; Adult; Affect; Anabolism; Autophagocytosis; Behavior; Brain; Brain Diseases; Buffers; Cellular Neurobiology; Child; Chronic; Clinical; Cognitive; Cognitive deficits; Data; Dendrites; Development; Education; Embryo; Energy Metabolism; Erythrocytes; Ferritin; Functional disorder; Growth; Health; Heme; Hemoglobin; Hippocampus (Brain); Homeostasis; Human; Impairment; In Vitro; Iron; Iron Overload; Knockout Mice; Learning; Life; Longevity; Lysosomes; Mediating; Memory; Memory impairment; Mental Health; Mental disorders; Metabolic; Metabolism; Mitochondria; Modeling; Morphology; Motor Skills; Mus; Neonatal; Nervous System Trauma; Neurologic; Neurons; Newborn Infant; Nuclear Receptor Coactivator 4; Occupations; Oxidative Stress; Play; Pregnant Women; Probability; Process; Proteins; Receptor Cell; Recording of previous events; Regulation; Research; Respiration; Risk; Rodent; Role; SLC11A2 gene; Site; Societies; Source; Structural defect; Structure; Synaptic plasticity; System; Testing; Time; Transgenic Mice; Translating; Up-Regulation; age related; cost; critical period; cytotoxic; cytotoxicity; extracellular; fetal; hippocampal pyramidal neuron; in vitro Model; in vivo; iron deficiency; neonate; neurobehavioral; neuron development; novel; novel therapeutic intervention; postnatal; prevent; protein complex; psychosocial; public health relevance; receptor; stem; synaptogenesis; uptake

ABSTRACT: Developing neurons have high iron requirements to support their metabolism, growth, and differentiation. Yet, free iron can produce oxidative stress and be cytotoxic. To avoid neurological damage from iron deficiency (ID) and overload, neuronal iron levels must be tightly regulated. Ferritin protein complexes play a critical role in regulating intracellular iron availability by storing iron that is not immediately used. During times of high iron demand (e.g., development), ferritin iron release must be controlled to prevent ID. Ferritinophagy, the process by which iron is released from ferritin and delivered to sites of high iron demand (e.g., mitochondria), was recently characterized in developing red blood cells (RBCs). Nuclear receptor coactivator 4 (NCOA4) is the specific cargo receptor that initiates mobilization of ferritin iron by directing ferritin to lysosomes via selective autophagy. Ferritinophagy is critical for maintaining the supply of iron required for mitochondrial heme synthesis in developing RBCs. There are currently no data on the role of NCOA4 or ferritinophagy during neuron development, causing a significant gap in our understanding of how the release of iron stored in ferritin is regulated during this highly iron-sensitive process. Dysregulation of neuronal ferritinophagy could result in severe iron underload or overload with significant clinical ramifications. This proposal focuses on early-life ID because it is prevalent throughout the world and permanently impairs neurobehavioral function (e.g., learning and memory) in children. ID specifically within the developing hippocampal neuron accounts for a significant portion of the learning/memory deficits. Basic principles of ferritin iron regulation discovered in this neuronal subtype will likely apply to all rapidly developing neurons. We hypothesize that, similar to iron handling during RBC development, iron released through NCOA4-mediated ferritinophagy forms an iron pool that is that is essential for normal neuron development and function. Aim 1 uses our unique in vitro model of chronic early-life hippocampal neuronal ID to test whether NCOA4 and ferritinophagy are required for optimal neuronal development by regulating iron availability. We hypothesize that loss of NCOA4 will disrupt neuronal iron homeostasis and impair critical neurodevelopmental processes (i.e., mitochondrial respiration, neuronal dendrite and synapse formation). Aim 2 translates Aim 1’s in vitro findings to the in vivo brain to reveal the developmental age-dependent role of NCOA4 and ferritinophagy in regulating hippocampal neuron iron utilization. We hypothesize that NCOA4-mediated ferritinophagy provides a source of iron that is required during the postnatal switch from iron storage to utilization and when neuronal iron supply is restricted (i.e., ID). We will test this using two unique hippocampal-specific transgenic mouse lines that model disruptions to neuronal iron uptake (Slc11a2 KO) or storage (Ncoa4 KO). Findings from the proposed studies will shift the current paradigm of how neuronal iron homeostasis is controlled during development, opening up a wealth of new research avenues with the potential to inform new therapeutic strategies for common iron-related brain disorders.

摘要：发育中的神经元对铁的需求很高，以支持其新陈代谢、生长和发育。 分化然而，游离铁可产生氧化应激并具有细胞毒性。为了避免神经损伤 铁缺乏（ID）和过载，神经元铁水平必须严格调节。铁蛋白蛋白复合物发挥着 通过储存不立即使用的铁，在调节细胞内铁可用性中起关键作用。的时间期间 高铁需求（例如，发育），必须控制铁蛋白铁的释放以防止ID。铁蛋白吞噬， 铁从铁蛋白中释放并输送到高铁需求部位的过程（例如，线粒体）， 最近的特点是发展红细胞（RBC）。核受体辅激活因子4（NCOA 4）是一种 一种特异性货物受体，通过选择性地将铁蛋白导向溶酶体来启动铁蛋白铁的动员 自噬铁蛋白吞噬对于维持线粒体血红素合成所需的铁供应至关重要 发展红细胞。目前还没有关于NCOA 4或铁蛋白吞噬在神经元凋亡中的作用的数据。 发展，造成了一个显着的差距，我们的理解如何释放铁储存在铁蛋白是 在这个高度铁敏感的过程中受到调节。神经元铁蛋白吞噬失调可导致严重的 铁负荷不足或过量，具有显著的临床后果。这项建议的重点是早期生活的ID，因为 它在全世界普遍存在并且永久地损害神经行为功能（例如，学习和 记忆）在儿童。特别是在发育中的海马神经元内的ID占很大一部分 学习/记忆缺陷。在这种神经元亚型中发现的铁蛋白铁调节的基本原理将 可能适用于所有快速发育的神经元。我们假设，类似于RBC过程中的铁处理， 在发育过程中，通过NCOA 4介导的铁蛋白吞噬释放的铁形成了一个铁库，这是必不可少的 正常的神经元发育和功能。Aim 1使用我们独特的慢性早期生命体外模型 海马神经元ID以测试最佳神经元ID是否需要NCOA 4和铁蛋白吞噬。 通过调节铁的可用性来发展。我们假设NCOA 4的缺失会破坏神经元铁 稳态和损害关键的神经发育过程（即，线粒体呼吸，神经元树突 和突触形成）。Aim 2将Aim 1的体外发现转化为体内大脑，以揭示 NCOA 4和铁蛋白吞噬在调节海马神经元铁中的发育年龄依赖性作用 利用率我们假设NCOA 4介导的铁蛋白吞噬提供了一个铁的来源， 出生后从铁储存到利用的转换以及当神经元铁供应受到限制时（即，ID）。我们将 用两种独特的、对神经元铁产生干扰的转基因小鼠来测试这一点 摄取（Slc 11 a2 KO）或储存（Ncoa 4 KO）。拟议研究的结果将改变目前的范式 神经元的铁稳态在发育过程中是如何控制的， 有可能为常见的铁相关脑部疾病提供新的治疗策略的途径。